Relationship between circadian-dependent toxicity of 5-fluorodeoxyuridine and circadian rhythms of pyrimidine enzymes: possible relevance to fluoropyrimidine chemotherapy.

摘要: Previous studies in experimental animals and patients have suggested a circadian variation host toxicity following administration of 5-fluorodeoxyuridine (FdUrd) although the biochemical mechanisms are not fully understood. Thymidine kinase (TK; EC 2.7.1.21), initial enzyme thymidine-phosphorylation pathway, is first anabolism FdUrd. Dihydropyrimidine dehydrogenase (DPD; 1.3.1.2), rate-limiting pyrimidine catabolic pathway has been shown to be key FdUrd catabolism. The present study examined relationship between potential variations activity these enzymes. Initial Sprague-Dawley rats confirmed that time affected death rate other drug-related toxicities including loss body weight, diarrhea, bone marrow suppression, with least highest survival being observed receiving at 12:00 noon 4:00 p.m. greatest lowest midnight a.m. Statistical analysis revealed pattern (Cosinor analysis, P < 0.001). In subsequent same species, we simultaneously measured TK DPD activities several tissues various times over 24 h. Under standardized light conditions (lights on, 6:00 p.m.; lights off, a.m.), sampling 4-h intervals (4:00 8:00 a.m.; noon; p.m., midnight), was (P 0.0001, Cosinor analysis) marrow, intestinal mucosa, liver, spleen. group animals, liver also 0.0001) inverse compared (Pearson correlation 0.05). Further statistical indicated correlated inversely Based on above data, conclude may explain as varied. These results useful design improved chemotherapeutic regimens using time-modified